β-Microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice.

Abstract

Extensive studies indicate that β-amyloid (Aβ) aggregation is pivotal for Alzheimer's disease (AD) progression; however, cumulative evidence suggests that Aβ itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of β-microglobulin (βM) and Aβ that trigger neurodegeneration in AD. βM, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of βM aggravates amyloid pathology independent of MHC class I, and coaggregation with βM is essential for Aβ neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated βM depletion mitigates AD-associated neuropathology, and inhibition of βM-Aβ coaggregation with a βM-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify βM as an essential factor for Aβ neurotoxicity and a potential target for treating AD.